Anti-tumor Necrosis Factor-α Agents Research Articles

Biologics in Focus: A Comprehensive Review of Current Biological and Small Molecules Therapies for Crohn’s Disease in the United Arab Emirates (UAE)

Introduction: The management of Crohn’s disease (CD) in the Middle East, like in other parts of the world, is rapidly evolving with the introduction of novel advanced medical and biological therapies. In the United Arab Emirates (UAE), several biological therapies are used to achieve remission in severe and resistant cases of CD. We carried out a literature search to analyze the effectiveness and safety of biologic treatments currently licensed in the UAE. Methods: We searched the PubMed, Embase and Cochrane library databases from inception to January 2020 to identify relevant studies. Search terms were generated using established treatment guidelines for CD. We also manually searched the bibliographies of relevant literature to obtain additional papers. Results: Biologic and small molecule agents for CD include four core drug classes: anti-tumor necrosis factor-α agents (TNF-α), integrin receptor antagonists, Janus kinase (JAK) inhibitors and IL-12/IL-23 antagonists. All drug classes showed good efficacy and safety in managing patients with CD. Some drug classes had distinguishable side effect profiles. This included an increased lymphoma and tuberculous risk for TNF-α and integrin receptor antagonists. Many trials supported the effectiveness of these licensed drugs. Biologic agent intolerance was common; one-third of patients receiving TNF-α treatment will develop intolerance to that specific drug. Conclusions: Advanced medical therapies licensed in the UAE have proven to be safe and efficacious. Additional research is required to evaluate the safety and efficacy of newer biologics and biosimilars.

Biologics in Focus: A Comprehensive Review of Current Biological and Small Molecules Therapies for Crohn’s Disease in the United Arab Emirates (UAE)

Introduction: The management of Crohn’s disease (CD) in the Middle East, like in other parts of the world, is rapidly evolving with the introduction of novel advanced medical and biological therapies. In the United Arab Emirates (UAE), several biological therapies are used to achieve remission in severe and resistant cases of CD. We carried out a literature search to analyze the effectiveness and safety of biologic treatments currently licensed in the UAE. Methods: We searched the PubMed, Embase and Cochrane library databases from inception to January 2020 to identify relevant studies. Search terms were generated using established treatment guidelines for CD. We also manually searched the bibliographies of relevant literature to obtain additional papers. Results: Biologic and small molecule agents for CD include four core drug classes: anti-tumor necrosis factor-α agents (TNF-α), integrin receptor antagonists, Janus kinase (JAK) inhibitors and IL-12/IL-23 antagonists. All drug classes showed good efficacy and safety in managing patients with CD. Some drug classes had distinguishable side effect profiles. This included an increased lymphoma and tuberculous risk for TNF-α and integrin receptor antagonists. Many trials supported the effectiveness of these licensed drugs. Biologic agent intolerance was common; one-third of patients receiving TNF-α treatment will develop intolerance to that specific drug. Conclusions: Advanced medical therapies licensed in the UAE have proven to be safe and efficacious. Additional research is required to evaluate the safety and efficacy of newer biologics and biosimilars.

Next-Generation Anti-TNFα Agents: The Example of Ozoralizumab.

Biologic therapy involving anti-tumor necrosis factor-α (anti-TNFα) agents has fundamentally changed the management of patients with immune-mediated inflammatory diseases, including rheumatoid arthritis, thus benefiting many patients. Nevertheless, the inability of some patients to achieve low disease activity or clinical remission remains a major concern. To address such concerns, next-generation anti-TNFα agents that differ from the immunoglobulin G-format anti-TNFα agents that have been used to date are being developed using antibody-engineering technology. Their unique design employing novel molecular characteristics affords several advantages, such as early improvement of clinical symptoms, optimization of drug bioavailability, enhancement of tissue penetration, and a reduction in side effects. This holds promise for a new paradigm shift in biologic therapy via the use of next-generation anti-TNFα agents. Ozoralizumab, a next-generation anti-TNFα agent that was recently approved in Japan, comprises a variable region heavy-chain format. It has a completely different structure from conventional therapeutic antibodies, such as a small molecular size, an albumin-binding module, and a unique format that produces an avidity effect. Ozoralizumab exhibited rapid biodistribution into joints, provided attenuation of Fcγ receptor-mediated inflammatory responses, and had a high binding affinity to TNFα in non-clinical studies. In clinical trials, ozoralizumab yielded an early improvement in clinical symptoms, a sustained efficacy for up to 52 weeks, and an acceptable tolerability in patients with rheumatoid arthritis. This review focuses on the results of pre-clinical and clinical trials for ozoralizumab and outlines the progress in next-generation antibody development.

Clinical Characteristics of Cryopyrin-Associated Periodic Syndrome and Long-Term Real-World Efficacy and Tolerability of Canakinumab in Japan: Results of a Nationwide Survey.

We assess the clinical characteristics of patients with cryopyrin-associated periodic syndrome (CAPS) in Japan and evaluate the real-world efficacy and safety of interleukin-1 (IL-1) inhibitors, primarily canakinumab. Clinical information was collected retrospectively, and serum concentrations of canakinumab and cytokines were analyzed. A total of 101 patients were included, with 86 and 15 carrying heterozygous germline and somatic mosaic mutations, respectively. We identified 39 mutation types, and the common CAPS-associated symptoms corresponded with those in previous reports. Six patients (5.9% of all patients) died, with four of the deaths caused by CAPS-associated symptoms. Notably, 73.7% of patients (100%, 79.6%, and 44.4% of familial cold autoinflammatory syndrome, Muckle-Wells syndrome, and chronic infantile neurological cutaneous articular syndrome/neonatal onset multisystem inflammatory disease, respectively) achieved complete remission with canakinumab, and early therapeutic intervention was associated with better auditory outcomes. In some patients, canakinumab treatment stabilized the progression of epiphysial overgrowth and improved height gain, visual acuity, and renal function. However, 23.7% of patients did not achieve inflammatory remission with crucial deterioration of organ damage, with two dying while receiving high-dose canakinumab treatment. Serological analysis of canakinumab and cytokine concentrations revealed that the poor response was not related to canakinumab shortage. Four inflammatory nonremitters developed inflammatory bowel disease (IBD)-unclassified during canakinumab treatment. Dual biologic therapy with canakinumab and anti-tumor necrosis factor-α agents was effective for IBD- and CAPS-associated symptoms not resolved by canakinumab monotherapy. This study provides one of the largest epidemiologic data sets for CAPS. Although early initiation of anti-IL-1 treatment with canakinumab is beneficial for improving disease prognosis, some patients do not achieve remission despite a high serum concentration of canakinumab. Moreover, IBD may develop in CAPS after canakinumab treatment.

Severe ulcerative colitis induced by COVID-19 vaccination

A 37-year-old woman developed severe colitis with diffuse mucosal erythema and ulcerations throughout the entire colon after the 3rd vaccination of COVID-19. Stool culture was negative, and the pathological findings showed increased lymphoplasmacytic and neutrophilic infiltration in the colonic lamina propria, which were consistent with ulcerative colitis. After the treatment with anti-tumor necrosis factor-α agent, the ulceration markedly improved with development of severe colonic stenosis, which was successfully dilated with endoscopic balloon dilation. In case of COVID-19 vaccination, it should be noted that vaccination could be a trigger for the onset of UC.

Rates of Adverse Events in Patients With Ulcerative Colitis Undergoing Colectomy During Treatment With Tofacitinib vs Biologics: A Multicenter Observational Study.

Patients with ulcerative colitis (UC) receiving immunosuppressive drugs are at substantial risk of colectomy. We aimed to assess the risk of postoperative complications of tofacitinib exposure before colectomy in comparison with biologics. A multicenter, retrospective, observational study was conducted in patients with UC who underwent total colectomy for medically refractory disease, exposed to tofacitinib or a biologic before surgery. Primary outcome was the occurrence of any complication within 30 (early) and 90 (late) days after surgery. Secondary outcomes were the occurrence of infections, sepsis, surgical site complications, venous thromboembolic events (VTE), hospital readmissions, and redo surgery within the same timepoints. Three hundred one patients (64 tofacitinib, 162 anti-tumor necrosis factor-α agents, 54 vedolizumab, and 21 ustekinumab) were included. No significant differences were reported in any outcome, except for a higher rate of early VTE with anti-tumor necrosis factor-α agents ( P = 0.047) and of late VTE with vedolizumab ( P = 0.03). In the multivariate analysis, drug class was not associated with a higher risk of any early and late complications. Urgent colectomy increased the risk of any early (odds ratio [OR] 1.92, 95% confidence interval [CI] 1.06-3.48) complications, early hospital readmission (OR 4.79, 95% CI 1.12-20.58), and early redo surgery (OR 7.49, 95% CI 1.17-47.85). A high steroid dose increased the risk of any early complications (OR 1.96, 95% CI 1.08-3.57), early surgical site complications (OR 2.03, 95% CI 1.01-4.09), and early redo surgery (OR 7.52, 95% CI 1.42-39.82). Laparoscopic surgery decreased the risk of any early complications (OR 0.54, 95% CI 0.29-1.00), early infections (OR 0.39, 95% CI 0.18-0.85), and late hospital readmissions (OR 0.34, 95% CI 0.12-1.00). Preoperative tofacitinib treatment demonstrated a postoperative safety profile comparable with biologics in patients with UC undergoing colectomy.

Tissue markers may predict treatment response to antitumor necrosis factor-α agents in children with Crohn's disease.

Patients with moderate-severe Crohn's disease (CD) who are treated with antitumor necrosis factor alpha (TNF-α) agents may be subjected to primary nonresponse or partial response. We aimed to identify tissue markers that may predict response to these agents. Pediatric patients (6-18 years) with either ileal or ileo-colonic CD who were treated with anti-TNF-α were stratified into three different groups based on their overall response to therapy at the end of induction including clinical and laboratory parameters (group 1-full responders [FR], group 2-partial responders [PR], group 3-nonresponders [NR]). Seven tissue markers (fibronectin, interleukin [IL]-23R, IL-23, TNF-α, collagen-III, IL-13R, and hypoxia-inducible factors [HIF]-1α) were evaluated. Immunofluorescence (IF) analyses were performed on biopsies from the terminal ileum, which were retrieved up to 6 months before treatment initiation. Twenty-six CD patients (16 [61.5%] males; age 13.9 ± 2.9 years), including 8 (30.8%) with ileal disease and 18 (69.2%) with ileo-colonic disease, were enrolled. Terminal ileum biopsies from nine patients from group 1, nine from group 2, and eight from group 3 were evaluated. Three antibodies were found to be significantly different between NR and FR groups; Collagen III and fibronectin stains were significantly more prominent in NR patients, while TNF-α stain was significantly more pronounced in FR, p < 0.05 for each. PR could not have been predicted with neither of markers. Decreased tissue IF intensity of fibronectin and collagen III and increased intensity of TNF-α may predict response to anti-TNF-α treatment.

Treatment in Patients with Psoriatic Disease and Rheumatoid Arthritis: Seven Case Reports

The incidence of psoriasis, an intractable long-lasting inflammatory skin disease, is increasing and has many complications and comorbidities. Approximately 14% of patients have psoriatic arthritis (PsA). Rheumatoid arthritis (RA) is not a rare disease worldwide, and some patients may have both PsA and RA. In the present study, we encountered seven patients with concurrent diagnoses of RA and psoriatic disease and reported the details of clinical data, treatment efficacy, and X-ray findings. The diagnosis may require not only classification criteria but also a comprehensive judgment in collaboration with rheumatology over time. In addition to methotrexate as an anchor drug, anti-tumor necrosis factor-α agents are the first choice of biological agents for treatment, and interleukin (IL)-17 inhibitors may be effective, as IL-17 is also involved in the pathogenesis of RA. When treating patients with both PsA and RA, it may be essential to consider the treatment strategy, depending on which disease is more active.

Updates on conventional therapies for inflammatory bowel diseases: 5-aminosalicylates, corticosteroids, immunomodulators, and anti-TNF-α.

The incidence and prevalence of inflammatory bowel diseases (IBDs) are rapidly increasing worldwide. IBDs are considered an emerging problem not only in Western countries but also in developing counties. The relapses and complications of active IBD mandate various medications. Nevertheless, hospitalization, emergency room visits, or surgery may be required, resulting in a socioeconomic burden. Great advances have been made in the development of new therapeutic options for IBD to achieve induction and maintenance remission. Nevertheless, conventional therapy is still the mainstay in the treatment of IBD. This review article provides an update on recent advances in conventional therapies, including 5-aminosalicylates, corticosteroids, immunomodulators, and anti-tumor necrosis factor-α agents to treat IBD.

Real-life experience of infliximab biosimilar in pediatric-onset inflammatory bowel disease: data from the Sicilian Network for Inflammatory Bowel Disease.

To provide data on the use of infliximab biosimilars (IFX-BioS) in children with inflammatory bowel disease (IBD). A multicenter, observational, retrospective study was performed among the cohort of the Sicilian Network for IBD. All consecutive IBD children who had at least completed the induction with IFX-BioS from its introduction in Sicily to January 2021 were enrolled. Clinical remission at weeks 14 and 52, treatment persistence, and adverse events were the study outcomes. Eighty-seven patients [Crohn's disease (CD): 57.5% and ulcerative colitis (UC): 42.5%] were included: 75 (86.2%) were antitumor necrosis factor-α (anti-TNF-α) agent naïve, while three (3.45%) were switched from the originator to IFX-BioS. Twenty (23%) patients were multiply switched from the biosimilar CT-P13 to SB2 or GP1111 or vice versa. The median follow-up time was 15 months. Clinical remission was achieved by 55.2 and 65.5% of patients at weeks 14 and 52, respectively, with no differences between CD and UC. Dose escalation was needed in 8.0 and 35.7% of patients during induction and maintenance, respectively. Nine adverse events occurred (incidence rate: 6.13/100 person-year). Treatment persistence was 90.8% at 1 year and 75.7% at 2 years (patients on IFX-BioS at 2 years, n = 28). The risk of treatment discontinuation was higher in patients with extraintestinal manifestations ( P = 0.018) and in those who were nonnaïve to anti-TNF-α ( P = 0.027). This is the largest cohort of pediatric IBD patients treated with IFX-BioS. Real-life data show that IFX-BioS is efficacious in IBD children, with high percentages of treatment persistence and a low incidence of nonserious adverse events.

Monoclonal Antibody Therapy for the Treatment of Interstitial Cystitis.

An emerging theory regarding the potentially autoimmune nature of painful bladder syndrome/interstitial cystitis (PBS/IC) had led to several studies being conducted to assess the possible therapeutic effect of immunotherapeutic options for PBS/IC. This review presents the available evidence regarding the potential autoimmunity-based pathogenesis of PBS/IC and focuses on a main representative of the immunotherapeutic modalities for PBS/IC, aiming to summarize, evaluate, and present available data regarding the potential therapeutic role of monoclonal antibodies for PBS/IC patients. A non-systematic narrative and interpretative literature review was performed. The monoclonal antibodies included in the review were the anti-tumor necrosis factor-α (anti-TNF-α) agents adalimumab, which showed no difference compared to placebo, and certolizumab pegol, which showed statistically important differences in all outcome measures compared to placebo at the 18-week follow-up visit. Anti-nerve growth factor (anti-NGF) agents were also reviewed, including tanezumab, which showed both positive and negative efficacy results compared to placebo, and fulranumab, the study of which was discontinued owing to adverse events. In summary, monoclonal antibody therapy remains to be further researched in order for it to be proposed as a promising future treatment option for PBS/IC.

Microbial changes in stool, saliva, serum, and urine before and after anti-TNF-\u03b1 therapy in patients with inflammatory bowel diseases

Inflammatory bowel diseases (IBD), including Crohn’s disease and ulcerative colitis, are chronic immune-mediated intestinal inflammatory disorders associated with microbial dysbiosis at multiple sites, particularly the gut. Anti-tumor necrosis factor-α (TNF-α) agents are important treatments for IBD. We investigated whether microbiome changes at multiple sites can predict the effectiveness of such treatment in IBD. Stool, saliva, serum, and urine biosamples were collected from 19 IBD patients before (V1) and 3 months after (V2) anti-TNF-α treatment, and 19 healthy subjects (control). Microbiota analysis was performed using extracellular vesicles (EVs; all four sample types) and next-generation sequencing (NGS; stool and saliva). The stool, using NGS analysis, was the only sample type in which α-diversity differed significantly between the IBD and control groups at V1 and V2. Relative to non-responders, responders to anti-TNF-α treatment had significantly higher levels of Firmicutes (phylum), Clostridia (class), and Ruminococcaceae (family) in V1 stool, and Prevotella in V1 saliva. Non-responders had significantly higher V2 serum and urine levels of Lachnospiraceae than responders. Finally, Acidovorax caeni was detected in all V1 sample types in responders, but was not detected in non-responders. Microbiome changes at multiple sites may predict the effectiveness of anti-TNF-α treatment in IBD, warranting further research.

Hyperactive neutrophil chemotaxis contributes to anti-tumor necrosis factor-α treatment resistance in inflammatory bowel disease.

Background and AimAnti‐tumor necrosis factor‐α (anti‐TNF‐α) agents have been used for inflammatory bowel disease; however, it has up to 30% nonresponse rate. Identifying molecular pathways and finding reliable diagnostic biomarkers for patient response to anti‐TNF‐α treatment are needed.MethodsPublicly available transcriptomic data from inflammatory bowel disease patients receiving anti‐TNF‐α therapy were systemically collected and integrated. In silico flow cytometry approaches and Metascape were applied to evaluate immune cell populations and to perform gene enrichment analysis, respectively. Genes identified within enrichment pathways validated in neutrophils were tracked in an anti‐TNF‐α‐treated animal model (with lipopolysaccharide‐induced inflammation). The receiver operating characteristic curve was applied to all genes to identify the best prediction biomarkers.ResultsA total of 449 samples were retrieved from control, baseline, and after primary anti‐TNF‐α therapy or placebo. No statistically significant differences were observed between anti‐TNF‐α treatment responders and nonresponders at baseline in immune microenvironment scores. Neutrophil, endothelial cell, and B‐cell populations were higher in baseline nonresponders, and chemotaxis pathways may contribute to the treatment resistance. Genes related to chemotaxis pathways were significantly upregulated in lipopolysaccharide‐induced neutrophils, but no statistically significant changes were observed in neutrophils treated with anti‐TNF‐α. Interleukin 13 receptor subunit alpha 2 (IL13RA2) is the best predictor (receiver operating characteristic curve: 80.7%, 95% confidence interval: 73.8–87.5%), with a sensitivity of 68.13% and specificity of 84.93%, and significantly higher in nonresponders compared with responders (P < 0.0001).ConclusionsHyperactive neutrophil chemotaxis influences responses to anti‐TNF‐α treatment, and IL13RA2 is a potential biomarker to predict anti‐TNF‐α treatment response.

Essential updates 2020/2021: Colorectal diseases (benign)-Current topics in the surgical and medical treatment of benign colorectal diseases.

The development of new drugs for inflammatory bowel disease (IBD) is remarkable, and treatment strategies using multiple agents and various techniques are required; however, the treatment strategy is likely to be complex. Therefore, appropriate evaluation of traditional surgical treatment strategies and accurate knowledge of the efficacy and limitations of novel treatments are required. Total infectious complications were found to be associated with the use of corticosteroids and anti‐tumor necrosis factor‐α agents, but not with immunomodulators, anti‐integrin agents, and 5‐aminosalicylic acid. Regarding surgical procedures for IBD, conceived anastomosis methods, including Kono‐S for Crohn's disease stenosis, are associated with better outcomes than conventional techniques. Autologous cell transplantation for Crohn's fistulae has been shown to have a favorable outcome. Diverticulitis is increasing and will be treated more frequently in the future. Risk factors for the incidence of diverticulitis and differences in pathogenesis according to right or left side diverticulitis have been reported. Antibiotic therapy may be omitted for uncomplicated diverticulitis. Moreover, regarding surgical procedures, both bowel resection and anastomosis are associated with favorable short‐term outcomes, higher stoma closure rate, and superior medical economy compared to Hartmann's procedure. Risk factors for recurrence after diverticulitis surgery may provide better postoperative follow‐up. In this review, we explore the current topics of colorectal benign diseases, focusing on IBD and diverticulitis, based on clinical trials and meta‐analyses from 2020‐2021. This review consolidates the available knowledge and improves the quality of surgical procedures and perioperative management for IBD and diverticulitis.

ARTERIAL STIFFNESS AND WAVE REFLECTIONS IN PATIENTS WITH SERONEGATIVE SPONDYLOARTHROPATHIES TREATED WITH TUMOR NECROSIS ALPHA BLOCKERS

Objective: The seronegative spondyloarthropathies (SpA) are a group of rheumatic disorders characterized by oligoarticular arthritis, enthesitis and axial involvement. Cardiovascular manifestations play a pivotal role in determining the excess mortality in SpA, owing to the linkage between systemic inflammation and accelerated atherogenesis. Arterial stiffness measured as carotid-femoral pulse-wave velocity (PWV) and wave reflections are validated markers of cardiovascular disease. Anti-inflammatory therapy with anti-tumor necrosis factor-α (TNFα) agents may have a role in reducing arterial stiffening in some disease models but data in patients with SpA are inconclusive. Design and method: Twenty-three patients with a short duration and high disease activity SpA (8 males, 15 females, mean age 53.9 ± 11.5 years) and without overt cardiovascular disease were enrolled. PWV and augmentation index (AIx, as a measure of wave reflections) were measured by a validated arterial tonometer (PulsePen, DiaTecne, Milan). Patients were compared with 23 controls matched for age, gender, blood pressure and heart rate. Arterial tonometry was repeated in 10 patients after 16 weeks of treatment with an anti-TNFα agent (Adalimumab, in 9 patients; Certolizumab, in 1 patient). Results: Of the patients enrolled, 14 had ankylosing spondylitis, 8 psoriatic SpA, 1 Crohn's disease-associated SpA. The median duration of the disease from diagnosis was 2 years (2–11 years). In the comparison with matched controls, no significant differences in PWV or AIx were found (PWV: SpA 8.9 ± 2.0 m/s, controls 9.2 ± 3.8m/s, p = 0.80; AIx: SpA 18.3 ± 14.7, controls 19.5 ± 12.0, P = 0.77). During the 16-weeks follow-up of patients treated with anti-TNFα therapy, despite significant improvement in disease activity parameters (ASDAS-CRP: 2.75 ± 0.8 to 1.67 ± 0.4, P &lt; 0.01; BASDAI: 5.05 ± 1.9 to 3,0 ± 1.2, P 0.05), no significant change was found in the hemodynamic parameters (PWV: 8.5 ± 1.8 to 9.7 ± 3.5 m/s, p = 0.11; AIx 16.6 ± 15.5 to 13.7 ± 10.0, p = 0.47). Conclusions: In patients with a short duration SpA, arterial stiffness and wave reflections are not significantly impaired. Anti-TNFα agents have no effects on arterial stiffness parameters in the short term, despite control of clinical and inflammatory burden. Forthcoming studies should explore the cardiovascular effects of novel therapeutics opportunities (anti-IL12/23 and anti-IL17) in patients with SpA.

Long-term efficacy and tolerability of dose-adjusted thiopurine treatment in maintaining remission in inflammatory bowel disease patients with NUDT15 heterozygosity.

Background/AimsThiopurines are key drugs for inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD). Recently, NUDT15 polymorphism (R139C, c.415C > T) has been shown to be associated with thiopurine-induced adverse events in Asian populations. In patients with the C/T genotype, low-dose thiopurine treatment is recommended, but its long-term efficacy and tolerability remain unclear. This study aimed to uncover the long-term efficacy and appropriate dosage of thiopurine for IBD patients with the C/T genotype.MethodsA total of 210 patients with IBD (103 UC and 107 CD) determined to have NUDT15 R139C variants were enrolled. Clinical data were retrospectively reviewed from medical records.ResultsOf 46 patients (21.9%) with the C/T genotype, 30 patients (65.2%) were treated with thiopurines. Three of whom (10.0%) discontinued thiopurine treatment due to adverse events and 27 of whom continued. The median maintenance dosage of 6-mercaptopurine was 0.25 mg/kg/day (range, 0.19–0.36 mg/kg/day), and 6-thioguanine nucleotides level was 230 (104–298) pmol/8 × 108 red blood cells. Cumulative thiopurine continuation rates for 120 months for patients with the C/C and C/T genotypes were not significantly different (P = 0.895). Cumulative non-relapse rates in the patients with UC treated with thiopurine monotherapy and surgery-free rates in CD patients treated with combination therapy (thiopurines and anti-tumor necrosis factor-α agents) for maintenance remission were not significantly different at 60 months (C/C vs. C/T, P = 0.339 and P = 0.422, respectively).ConclusionsLow-dose thiopurine treatment is an effective and acceptable treatment for patients with C/T genotype.

Serum PR3-ANCA Is a Predictor of Primary Nonresponse to Anti-TNF-α Agents in Patients with Ulcerative Colitis

Background: Anti-tumor necrosis factor-α (TNF-α) agents are effective for moderately to severely active ulcerative colitis (UC). Nonetheless, a proportion of patients fail to respond to these agents as therapy for induction of remission. Recent studies indicated that perinuclear anti-neutrophil cytoplasmic antibody (p-ANCA) may predict response to anti-TNF-α agents in UC patients. However, whether PR3-ANCA can predict primary nonresponse (PNR) to anti-TNF-α agents has not yet been evaluated. The aim of this study was to examine whether PR3-ANCA can predict PNR to anti-TNF-α in UC patients. Methods: This was a single-center retrospective study. Data were extracted from 50 patients with UC who had measurements of PR3-ANCA and received anti-TNF-α agents for the first time as induction therapy. The primary endpoint of this study was a proportion of patients with PNR stratified by PR3-ANCA positivity. PNR to anti-TNF-α agents was defined as failure to achieve reduction in partial Mayo score by 2 or more points and change to other therapeutics within 6 weeks. Results: Fourteen (28%) of the 50 patients were PR3-ANCA positive. Seventeen (34%) of the 50 patients demonstrated PNR. Eleven (78.6%) of the 14 PR3-ANCA-positive patients demonstrated PNR, while 6 (16.7%) of the 36 PR3-ANCA-negative patients demonstrated PNR. Multivariate analysis demonstrated that PR3-ANCA positivity was associated with PNR to anti-TNF-α agents (odds ratio 19.29, 95% CI: 3.30–172.67; p = 0.002). Conclusion: PR3-ANCA positivity can predict PNR to anti-TNF-α agents in UC patients.

Clinical characteristics of elderly and younger onset rheumatoid arthritis

Objective: To compare the clinical and laboratory characteristics and therapy methods of elderly onset rheumatoid arthritis (EORA) and younger onset rheumatoid arthritis (YORA). Methods: The clinical, laboratory and therapeutic data of 481 RA patients in the Department of Rheumatology and Immunology in Peking University Third Hospital from January 2013 to December 2018 were collected and used to analyze the difference of characteristics between EORA group and YORA group, which might be useful for better diagnosis and treatment of EORA patients. Quantitative data of normal distribution were compared with t test between the two groups. Results: There were 481 patients in this cohort, of which 137(28.5%) were EORA, 344(71.5%) were YORA, with a mean age of (59±14) years (19-87 years). There were 358 females (74.4%) and 123 males (25.6%). The percentage of male patients was obviously higher in EORA group (36.5% vs 21.2%, χ(2)=12.012, P<0.01), and the average disease course was obviously shorter (Z=-7.985, P<0.01). Disease Activity Score 28 (DAS28) score was higher in EORA group (5.6±1.3 vs 5.2±1.6, t=2.549, P<0.05), meanwhile the incidences of pleural effusion and interstitial lung disease (ILD) were higher (6.6% vs 1.7%, 29.9% vs 18.3%, respectively; χ(2)=7.550, 7.797, both P<0.05). The incidences of venous thrombosis, primary hypertension, diabetes mellitus, cerebrovascular disease, coronary heart disease (CHD), peripheral atherosclerosis and cataract in EORA group were all significantly higher than those in YORA group (all P<0.05). Erythrocyte sedimentation rate (ESR) and D-Dimer in EORA group were all remarkably higher (both P<0.05). The rate of using glucocorticoid in EORA group was higher but the rate of using methotrexate and anti-tumor necrosis factor-α agents were lower (χ(2)=5.271, 8.407, 9.356, all P<0.05). Conclusion: Compared to YORA group, the percentage of male patients and disease activity of EORA group are higher. The occurrence of pleural effusion, ILD, venous thrombosis, primary hypertension, diabetes mellitus, cerebrovascular disease, CHD, peripheral atherosclerosis and cataract in EORA group are higher than those in YORA group.

Extending the in vivo Half-Life of Adalimumab Fab via Sortase A-Mediated Conjugation of Adalimumab Fab with Modified Fatty Acids

AbstractAdalimumab, a full-length monoclonal antibody, is widely used as an anti-tumor necrosis factor-α (anti-TNF-α) agent. In this article, we aimed to prolong the in vivo half-life of adalimumab antigen-binding fragment (Fab) through Sortase A (SrtA)-mediated conjugation of its Fab with fatty acid (FA). In our study, adalimumab Fab analog was prepared by adding an SrtA recognition sequence (LPETGG) and His6 tag to the heavy chain C-terminal of the Fab via (G4S)3 linker. Four FA motifs with different linkers were designed and synthesized by solid-phase methodology, then conjugated with the Fab analog using SrtA to produce Fab bioconjugates. The successful generation of four Fab bioconjugates (Fab–FA1, Fab–FA2, Fab–FA3, and Fab–FA4) was confirmed by SDS-PAGE (sodium dodecyl sulfate polyacrylamide gel electrophoresis) and mass spectrometry. Then, the bioactivities and half-life of these Fab bioconjugates were examined using TNF-α-/human serum albumin (HSA)-binding enzyme-linked immunosorbent assay, cytotoxicity assay, and pharmacokinetic study, respectively. All Fab bioconjugates exhibited similar TNF-α-neutralizing activities when compared with the Fab analog, even in the presence of albumin, indicating that there were no apparent influences on the functional site of Fab after FA modification. However, different degrees of affinity for HSA were observed among these Fab–FA bioconjugates, with Fab–FA3 exhibiting the maximal affinity. An in vivo study in mice further revealed remarkably improved pharmacokinetics of Fab– FA3 with a 15.2-fold longer plasma half-life (19.86 hours) compared with that of the Fab analog (1.31 hours). In summary, we have developed a novel long-acting adalimumab Fab bioconjugate, Fab–FA3, with more sustained in vivo activity, which can be used for drug development targeting TNF-α-mediated inflammatory diseases.

Depression, Anxiety, Related Risk Factors and Cognitive Distortion in Korean Patients with Inflammatory Bowel Disease.

ObjectiveTo evaluate the severity of depression, anxiety, associated risk factors, and cognitive distortion in Korean patients with ulcerative colitis (UC) and Crohn’s disease (CD). MethodsThis study included 369 patients with inflammatory bowel disease. The severity of depression and anxiety was examined using Patient Health Questionnaire-9 and Hospital Anxiety and Depression Scale. The Anxious Thoughts and Tendencies scale was used to measure catastrophizing tendency. Multivariate regression analyses were performed. ResultsThe predictors of depression were marital status, anti-tumor necrosis factor-α (TNF-α) agent use, age, and body mass index in UC patients and marital status, disease activity, alcohol use, and employment status in CD patients. For anxiety, sex and marital status were the associated factors in UC patients, whereas steroid use was the only significant predictor in CD patients. Comparing the cognitive distortion level, there were no significant differences between UC and CD patients although there was an increasing tendency according to the severity of depression or anxiety.ConclusionIf patients are accompanied by high levels of depression or anxiety and their associated risk factors including TNF-α agent or steroid use, it is recommended that not only symptoms are treated but also cognitive approach and evaluation be performed.